 Thank you. And so, you know, as I get started, I just wanted to share a quick story with everyone that I myself am a cancer survivor. I had a melanoma that was diagnosed on my face when I was a resident and my wife had just given birth to our first daughter. And it was just an absolutely terrifying process. I met with several different surgeons, had several different consultations. And while I spoke the medical language, it was still all confusing and overwhelming. And I really wanted to base this talk and I really created a brand new slide deck for this individual meeting with the hope of just making everything as transparent as possible. Try to remove as much doctor speak as I possibly could. And if questions are emerging either during the talk or after, I'm happy to take any questions that come out. So it really is my honor to be here today. This is a complex topic because I believe we really are just scratching the surface of immunotherapy and immuno-oncology. There are a lot of agents that are coming down that are very exciting, that by themselves may not have a huge role, but in combinations may prove to be tremendous game changers. So the title of my talk, Why does immunotherapy not work for everyone? What are predictors of success? Can patients be cured? Disclosures? And so as we've discussed and you have heard so far prior to 2005, our surgeons played the biggest role by far in managing of this cancer and they still very much do. From the medical oncologist perspective, what could we add was cytokine-based therapy. And these are basically therapies that made people feel like they had the flu. And they really were an all-or-none phenomenon. They worked for some, about five to seven percent of patients who received high-dose narrow-leukin-2 with Medisac disease would never relapse again, and they were cured with a very intensive but short period of time. However, during the initial studies, one percent of patients who were treated died from being treated. And so when you think about five to seven percent cure or with one percent risk of death, that's a very, very narrow window. Chemotherapy had been tried and deemed a failure. Radiation had been tried and at the time, conventional radiation had not shown any effect. And this is one of the slides, and I'm going to show very few of these Kaplan-Meier curves, and basically if you look at the y-axis, which is the one that goes from top to bottom, a hundred percent of people are alive when you start, zero percent, and this is for continuing a response. So a hundred percent of patients are at the top, zero percent of patients are responding, and then duration on the x-axis at the bottom is in months. And what you can see here is the patients that have the complete response. One of these patients are never going to have recurrence of disease up to ten years after. However, I caution everybody in the room, including the medical oncologists in the room and the surgeons, you can see that patients even in complete response, there were patients that relapsed. And while we are very excited about the complete response that's being seen with the combinations of immunotherapy, until we have longer-term follow-up, we can't call all of those patients cured. And that's important. So clear cell renal cell. Others have shown this, but this is, Amisha and I, when we have patients come into clinic, we draw this out. And I think about this in very simplistic terms. So if you look at a clear cell cancer cell, VHL, and so VHL basically is gene, gene was discovered in the 1980s and was named after two famous scientists that were working on kidney cancer. This gene produces a protein also called VHL, and this controls and regulates HIF. HIF is your oxygen sensor in cells. So in 90% of clear cell renal cell carcinoma, VHL is lost. These are both the familial type, which is the VHL syndrome. And in also sporadic cases, and it can be lost in a variety of ways. It can be silenced. The protein itself can be malformed. There's a lot of different ways that this can be impacted. But when it's lost, what happens? HIF starts building up. And so basically your cell is signaling that I don't have enough oxygen. So it goes into the nucleus and it spits out growth factors. So think about these like fertilizer for where the tumor lives. And so one of the most famous is VEGF. And VEGF stands for vascular, which are blood vessels. And ethereal, which are blood vessel lining cells. And growth factor again is fertilizer. On all these blood vessel cells, they have receptors that are looking for this signal. And this causes these blood vessels to continually sprout and form new blood vessels, which is why clear cell kidney cancer is an extremely vascular tumor. We can block VEGF with Bevisizumab. We can block these with a variety of different TKI's. And so in the era of 2005 to 2015, this was where the real progress was made. So the immune system is incredibly complex. But trying to break this down into more simplistic terms, we have an innate immune system. And so if you go all the way back to flies and insects and then earlier lizards, you're going to see innate immune system. And then in more advanced species, including humans, you begin having the adaptive immune system. So the innate immune system, neutrophils, these are your first responders. Anytime there's some bad looking cell, the neutrophils rush in. They release a lot of chemicals. And this is why when you get a cold, your initial days are pretty miserable as they're secreting everything, trying to control it. Macrophages, these are the eaters of damaged cells. Eosinophils, they help you target parasites and allergies. The reason why I think we have so many allergies these days is we live in a world where we disinfect everything. We no longer have parasites. So our eosinophils don't know what to do with themselves. Dendritic cells, these are cool cells. These basically help pick up dying cells and debris. And their goal is to show off to T cells what they've found. In between we have these natural killer cells and there's a lot of really exciting research looking at these. Their goal is to recognize self versus alien. And so if you're a cell that's not supposed to be there, their goal is to take care of it. The adaptive immune system, these are B cells. And the B cells, when they're triggered, produce plasma cells which are antibody factories. And then we have T cells and these are the smart killers. There's a very delicate balance because you can have malfunction on both sides. Overactivation. And so I think about tuberculosis. Tuberculosis kills people because you have an infection that the body is trying to control and contain and just cannot. But the reason why it was called consumption for many years was because you would consume everything in your body, all of your energy stores trying to get rid of it. Overactive can also be due to inflammatory conditions like autoimmune diseases such as rheumatoid arthritis and lupus. We also see inflammatory conditions lead to cancer. So ulcerative colitis has a very high rate of colorectal cancer. Underactive, death due to infections, inability to heal wounds, and also potential development of cancer. So there is this, how do we achieve this balance? There is an incredibly complex communication that occurs between cells, tissues, organs. Chemical signals are constantly being sent out trying to make sure that everything is in status quo. Some of these signals stimulate the immune systems while others will knock it down. Some of the immune cells are active in targeting cells and others actually suppress cells. The amazing thing is everything is plastic and so cells can change from one to another depending on their environment. And so part of our issue with all of this is when we get a sample, even if it's a tissue biopsy, we're seeing a window of time. We're not seeing the evolution. When I'm showing at the bottom where it's just M, that's again the macrophage. And this is way oversimplified because as we continue to explore, we continue to find more and more subtypes for macrophages. But in simple terms, M1 tend to be good macrophages that you want to have around M2 are negative regulators of the immune system. T cells, there's a variety of T cells. T cells became very imprinted in everyone's mind during the HIV epidemic. And we think about T1, these are CD8 T cells and T2, these are CD4 T cells. CD4 are the ones that are targeted by HIV. We also think about these T1 cells as being our T effector cells. And then we can have T regulatory cells. Again, these are ones trying to help suppress the immune response, which is good because you don't want to have an immune system that's again always turned on. But cancer finds a way to cause these regulatory cells to help keep away the good immune cells from targeting the cancer cells. All right, so let's briefly talk about T cells. And so when we're all growing up in our very early stages after we're born, we're born with a thymus. And most of us have had our thymus disappear by adulthood. But during the time in the thymus, these baby T cells and I made them a little T are constantly being exposed to self-antigens. And if they react to self-antigens, they're removed because you do not want to attack yourself. You want to attack things that are foreign. And we literally have millions of T cells that then eventually are able to make their way out. Most of these T cells are either at times in circulation. We have T cells that end up in the gut. Those are a little different than the standard T cells. We also have T cells that make it into lymph nodes. So let's think about the common cold. So the common cold, we have infected cells that are virally infected. And these cells are trying to figure out ways to get a flag up that says, help me. And so what happens? You get this Russian of the innate immune system shown here in purple and yellow. These are some of the antigens that are inside these virally infected cells. And what this flag at the top is, is one of these antigens that's being brought up to the surface. So you get this Russian of these killers or these neutrophils. And these cells can die in a variety of ways. These cells can die by something that's called apoptosis, which is the shrinking of these cells, which then can be munched up by the macrophages. You can also die from necrosis. Necrosis is the split opening of these cells, which is much more immune-stimulating. Dendritic cells can pick up debris. There's a release of cytokines and chemokines. These are chemicals that help sound the alarm. We have learned over time, and Jim Allison did a lot of this work during his time at a variety of places. He's now the chair of our immunology department at MD Anderson. But these signals are, the dendritic cell has to present its antigen to the T cell. There also has to be a second signal that allows these T cells to activate. And this signal is between CD28 on T cells and CD8 on these dendritic cells, or what's known as professional antigen presenting cells. If the signal occurs, this resting T cell can turn into an effector T cell and have some of these then go kill the virus, and then there's a potential to generate memory. And if you generate memory, this is why if you're exposed to the same infection again, you're unlikely to get it. And that's why vaccines in general have been the greatest thing that has ever come out to help protect the population as a whole against things like polio and measles and other infections that killed many, many patients and children. However, when CD28 comes up, CTLA4 comes up soon after. And it blunts that immune response, because again, you want to be sure that this is worth going after. We can block CTLA4, and this is your ipolumimab, which has been discussed earlier, and other agents that have been in testing as well. And when this is blocked, again, you have the better chance to then generate these T effector cells and potentially that immune response as well. The PD1, PDL1, which has been talked about, PD1 is Program Death Leg, or Program Death Receptor 1 and Program Death Leg into 1. And so these are mostly in the tumor microenvironment. The CTLA4 is more on lymph nodes, and so it's considered an earlier event. And so I really liked Mike's slide earlier today with the police officer, because I think that's really true. You really helped get more of those police officers in with CTLA4, but the police officers that are there are helped by this PD1, PDL1 interaction. So I think about the PDL1 as a camouflage for the tumor. The other thing, and I'll show this a little bit later, is PDL1 can also be on effector T cells, or also on other immune cells in its environment. Those are basically a sleepy, exhausted signal. So kidney cancer still is a little bit simpler, because we have nivolumab here, but I also treat patients with bladder cancer. And in bladder cancer, we have five agents that all are attacking the same pathway. So we have PD1, and then we have PDL1 antibodies. All of these, there's a variety of these that are also currently in testing in renal cell, and there's a good chance that some of these drugs may come online in the not too distant future. So where do we stand with immunotherapy in 2018 for kidney cancer? So op-divo, or nivolumab, approved in 2016. It improved survival as compared to patients who are treated with ephrolimus, which is an mTOR inhibitor. In patients with metastatic clear cell kidney cancer, 22% of patients had response. I don't think that's the whole story, because we really believe that more patients than 22% have benefit. The issue with response is when we think about response on cancer trials, that means that patients have to have a 30% reduction in their cancer burden measurements when we take measurements. This was developed in the era of chemotherapy, and it doesn't apply as well to immunotherapy. The side effect profile of nivolumab was very reasonable. 8% of patients had to stop therapy due to major side effects. And when they looked at tolerance, it has compared to ephrolimus, who was much better tolerated. So nivolumab plus ipoluumab was approved earlier this year, and that was actually a typo. This is 2018, not 2017, and it's based on the Checkmate 214 study. And so patients on this study were given either nivolumab, nipoluumab, or given sunitinib. 42% of patients had response. However, when you compare the rate of patients that had major events, 22% of patients had to stop therapy due to serious immune related toxicities. We are very excited about a lot of the combinations that are quickly coming down the pike that are combining the VEGF TKI therapies with immunotherapy. The response rates that we have seen in phase one and two studies have been very high. And multiple phase three studies are soon to be reporting, and there are going to be some that will be reported at a conference in October, which is the ESMO or European Society of Medical Oncology. So can we predict response? The answer really is no, we're still having a major problem here. It seemed really simple. This study led by Dr. Topalian, it seemed that if you had PDL positivity in cancer cells, your chance of responding was real, and we saw this across a variety of cancer types. This included melanoma, kidney cancer, lung cancer. If you're negative on this initial study, no response. We have learned over time, though, that that's just not the case. We're struggling in some ways because every company has a different companion biomarker. Everyone has a different antibody. Everyone is testing different things. Some companies are only testing tumor cells. Other companies are only testing the immune infiltrate for PDL positivity, and others are testing both. Even when the same company is testing and doing trials in different tumors, they're using different cut points. And even sometimes in the same type of cancer, they use different cut points. And when I say cut point, what does that mean? That means that a patient is considered positive if they have a 1% staining. And what I can tell you is if you sneeze on a slide, it can look at as 1% positive. Some companies are using 5%, some are using 10%, some are using 25%, so it's all very confusing. So the PDL status in kidney cancer. So this had been shown for a while that patients that have PDL positive tumors, and this is really in the era of the TKI's prior to the introduction of immune checkpoints, it was felt to be a negative prognostic marker. So what does that mean? Patients that were positive here were less likely to do well with treatment, or it meant that they basically had a worse overall outcome if they had this as part of their initial diagnosis on staining. And the Checkmate 025 was tested, which was, again, Nevolimab versus Everlimus. Patients in both groups did worse if they were PDL positive. It did not impact their likelihood to respond. And Nevolimab still did a little better than Everlimus on that side of things. So it was not decided that we should need to check patients for PDL positivity. Checkmate 214 looked encouraging because patients who had PDL positivity did better with immunotherapy as compared to synitinib, and patients appeared to have a higher rate of complete response if they were positive as compared to those who were negative. So perhaps we're overcoming the negative prognostic marker of the PDL positivity. This is still confusing to me because in melanoma it's the exact opposite conclusion. If PDL positivity was simple, all positive patients would respond and all negatives would not, but it's not so. And part of the reason why, and this is a very nice illustration by Pam Sharma and Jim Allison from MD Anderson, is PDL positivity is dynamic. And what does that mean? It means based on what a patient is receiving at that given time or based on what's going on in their body at that time, PDL can be positive or negative. So a patient can flip their status as being positive or negative. It is not static. The other thing that is so interesting is even if you sample multiple areas in the same patient at the same time, you may get a different result. What they're showing on the figure to the right is a tumor that is invaded by multiple different immune cells. These are called the hot tumors. And then at the top, these are considered cold tumors. And again, cold tumors are felt to be less likely suitable for just targeting PD1 or PDL1. I also treat patients with testicular cancer. And there a huge number of patients will be PDL positive, but we're not seeing any responses using PD1 or PDL1 agents. And it's because they have no immune cells there. I always like this slide. So this is an example in melanoma. Melanoma and kidney cancer have been cousins for a long time due to the use of high-dose interleukin-2. So I always like to keep track of what's going on in melanoma. So in melanoma, about 50% of patients who have cutaneous melanoma will have a BRAF mutation. And the first breakthrough drug that came out from metastatic melanoma was targeting BRAF. And what you can see here is in the top two slides, you see CD8 positive and CD4 positive. And the pink are the immune cells that have infiltrated into this tumor. Six weeks into treatment with this drug, which is a BRAF inhibitor, you see this massive influx of immune cells. And then when you see when the patient's cancer grows because patients will eventually lose the response with these drugs, all those immune cells are gone. And that tells you that you have a window to see what actually is going on within these tumors. And if a biopsy is done at progression, you may not learn why the patient is progressing. So I mentioned earlier that PDL can cause exhaustion in T cells. And so if we are able to target this again, we're able to potentially restore their functionality. But interestingly, what a tumor is secreting into its environment also is influencing PDL status. And there's been some very nice modeling that's come out that's showing that high levels of VEGF can cause effector T cells to produce PDL. So why do patients maybe not respond? Well, we've seen that effector T cells can malfunction. We need these T cells to be able to secrete their killing, basically their kill function. And one of their main kill functions is producing something that's called interferon gamma. And there's been some very nice work that has shown that these T cells can have a malfunction in that pathway so that they can't do their job. MIA means that they're missing in action. They're just not present. We've also found that there's many, many more checkpoints than just CTLA4 and PD1 and PDL1. From a tumor standpoint, what are we seeing? Tumors can evolve. They can figure out ways to get around and to bring up other immune checkpoints. Houdini, they can hide. They can do a better job of not showing off antigens that they may have. And they can continually work on camouflaging with other immune checkpoints. They can build up a fortress. They can bring in a lot of negative immune cells to help keep good immune cells out. And there's a potential that some organs in their environment may be worse. And we think this may be the case with potentially liver and bone and potentially brain. So what else is going on? So we're exploring if we can kill cells through various mechanisms, freezing and cooking, high-dose radiation to help cause some of this necrotic cell death to be more immune-stimulating. We're exploring additional pathways that may be important to kidney cancer. And we're trying to work on blood-based assays to hopefully try and limit biopsies as we move forward. So do we cure patients with modern immunotherapy? I'm going to give a couple of cases where I think the answer to this question is yes. So this is one of my patients, 66-year-old male who came in with fatigue, weight loss, not feeling well, very rapidly growing breast mass. And I don't know if my... But right here, this is a tumor. They actually, at the outside hospital, diagnosed him with triple negative breast cancer. So male breast cancer is something that we see quite commonly at MD Anderson. Somewhere around 95 to 99% is hormonally positive. So you're taking a rare cancer and even making it more rare. So he was referred to our breast group. They did additional workup. He had bone metastases, large kidney mass. He had tumor within the liver. So when I saw him, he was not feeling well. He had lost nearly 20 pounds, poor appetite, coughing, pain, having worsening anemia. He had elevated neutrophil count. He clearly had porous disease. We did a kidney biopsy extensive necrosis with clear cell features and that looked the same as the breast biopsy. So we actually put them on one of the clinical trials. And so this is a patient's breast mass. You can see it here and then see it melting away. You can see his baseline scan. And what I want you to look at here is see how in this tumor there's this white area and then this very dark area. This area right here, keep an eye on because that's what these tumors often look like, centrally necrotic. But when you look at it over time, that now just looks all the same. It looks very cystic in nature. You underwent surgery and sure enough, that entire large tumor, there was no viable tumor remaining after just six weeks of treatment. So that patient remained on therapy for a while. We eventually took him off because he had elevated pancreas enzymes and was developing some symptoms. He's been off of all therapy now for over 18 months and is doing remarkably well back to work full time. This is a second patient. Patient presented with hoarseness, not feeling well, very, very big burden of pulmonary metastases, large kidney primary in place, he had anemia, his calcium was quite high, not feeling well at all. He's also put on trial. He gets two doses of nevolumab and epilumab. His lung metastases melt. His kidney again becomes more cystic in nature. Minute focus of residual cancer with therapy effect at the time of surgery. Resumes nevolumab. We can virtually see no sign of his cancer. He's feeling great. So are these patients cured? We're very hopeful. Long-term data is lacking. And so we really want to be convinced as a community that these patients will continue these responses for a long time. And I think many questions remain. How long did treat the great responders? Are complete responders the same as the deep partial responders? And how do we select the best treatment for each patient? So the evolution of treatment since 2005 has been clearly astounding. And how do we learn and continue to improve? We have to trust each other. We have to partner together. We have to advocate. We have to fight. Every patient is an individual. You are not a stat. And we have to fight as a community. And what's the community? It's patients. It's their caregivers. It's physicians. It's nurses. It's pharmacists. It's everybody in the team. It's also our government. It's industry. Everybody plays an important role. And we make progress with government funding, industry and philanthropy. All agents that have been approved to date only made it by participation in clinical trials. And there remains substantial work to be done. But I feel that the future is truly bright in the fight against this cancer. And with that, I'll thank you. And I'm happy to take any questions.